Super elastic, bioabsorbable endovascular devices

ABSTRACT

The invention relates to endovascular medical implant devices and materials of composition for forming these devices to provide improved mechanical properties and biodegradability. The devices include a combination or integration of superelastic material, biodegradable metal and, thin film nitinol and/or biodegradable polymer. A structural frame is formed of individual elongated pieces composed of biodegradable metal. These pieces are joined together by connector pieces composed of superelastic material. At least a portion of the structural frame has deposited thereon the thin film nitinol and/or biodegradable polymer. The structural frame of the device is collapsible for insertion in a delivery tube and, recoverable for deployment and placement in a vascular location of a patient body.

CROSS REFERENCE TO RELATED PATENT APPLICATION

This patent application claims the benefit of U.S. Provisional PatentApplication No. 62/078,023, entitled “Super Elastic, BioabsorbableEndovascular Devices”, filed on Nov. 11, 2014, the contents of which areincorporated herein by reference.

1. FIELD OF THE INVENTION

The invention relates to super elastic, bioabsorbable endovasculardevices and materials of composition for these devices to provideimproved mechanical properties and biodegradability for implanting thedevices in a patient.

2. BACKGROUND

The introduction of minimally invasive surgical techniques and thedevelopment of various endovascular devices have substantially improvedhuman health care over several decades. Further improvements may berealized by increasing the functionality of these devices and extendingthe types of procedures where such devices may be employed.

It is believed that improvement in the materials of composition andconstruction of the endovascular devices will provide increasedopportunities for optimizing the benefits derived from the devices. Forexample, it is desired to utilize different materials to achieve bothimproved mechanical properties and biodegradability for medial implantdevices. The use of degradable components allows a tissue engineeringapproach to be pursued where no permanent foreign body is left behind inthe patient when there is no longer a need for the implanted medicaldevice. Devices or pieces of devices remaining in the patient canpotentially pose a risk of infection, fibrosis or abrasion. Constructingdevices from biodegradable materials can substantially reduce oreliminate these risks.

There are many known medical conditions and diseases wherein treatmentcan be improved by the development of improved materials for implantablemedical devices, including the following examples.

Pediatric Heart Valve Replacement Methods and Shortcomings

Heart valve disease is a condition in which the valve, which ispositioned between the main pumping chamber of the heart (leftventricle) and the main artery to the body (aorta), malfunctions. Heartvalve disease may be a congenital condition. For infants, defects incardiac valves and associated structures account for 25 to 30 percent ofall cardiovascular malformations. In adults, valvular heart diseaseremains a major cause of morbidity and mortality. For example,approximately 98,000 valve replacements were performed in the UnitedStates in 2006.

There are typically two types of prosthetic heart valves forreplacement, which are mechanical and bioprosthetic. Mechanical heartvalves are made entirely of synthetic materials such as metals andpolymers, while bioprosthetic heart valves are made of tissue fromanimal (e.g., bovine or porcine) or humans. Mechanical heart valves arevery durable, most lasting at least 20 to 30 years. However, thesevalves have limited central flow due to their designs such asbileaflets, the ball in cage, or tilting disc. In addition, one of themajor drawbacks is that mechanical heart valves require dailyanticoagulant treatment because of an increased risk of artificialmaterial induced thrombosis and thromboembolism.

Bioprosthetic heart valves have improved central blood flow due to theirbio-mimicking trileaflet design and do not require anticoagulanttherapy. However, these bioprosthetic heart valves also have associateddisadvantages, which include limited durability due to leafletcalcification, leaflet tearing, fatigue damage, and tissue failure.Therefore, it has been found that about 10 to 20 percent of homograftbioprostheses and 30 percent of heterograft bioprostheses fail within 10to 15 years of implantation, and require replacement.

In the pediatric population, in particular, failure of the mechanicaland biological valve replacement to grow, regenerate and remodel requiremultiple subsequent reoperations to place larger devices to accommodatesomatic growth. A tissue-engineered heart valve has been an elegantalternative to overcome the above-mentioned limitations.

The scaffolds utilized in heart valve tissue engineering includedecellularized xenografts/homografts and synthetic polymeric scaffolds.Depleted of cells and cellular components, xenografts/homografts possessmicro-structure, mechanical properties and physiological hemodynamicssimilar to their native counterparts. Further, signaling moleculesexisting in the scaffolds provide natural cues to guide cell adhesionand growth, and tissue formation and remodeling. Successfulrecellularization has been demonstrated in animal models usingdecellularized matrices. However, a significant concern is the severeimmunogenic response, which leads to early graft failure. In addition,it is controversial to implant xenografts in humans and, the use ofhomografts may raise ethical concerns and limited donors areproblematic. Therefore, the utilization of synthetic polymeric scaffoldalone is quite attractive, since the depletion of biological componentcan greatly reduce the potential immunogenic response and the materialsource is much more abundant and the handling is easier.

The main challenge of the synthetic scaffold is to recruit autologouscells, which have to differentiate into the appropriate phenotype toachieve tissue remodeling and heart valve functionality. Insufficientcellularization on a plain scaffold may result in thrombus formation andcalcification, and eventually lead to leaflet stiffening and tearing.Combining the synthetic scaffolds with collagen, cells, or ECM gel hasdemonstrated good cellular infiltration and tissue integration in boththe animal and clinical studies.

Furthermore, both mechanical and bioprosthetic heart valves require anopen heart surgery, which has a severe risk factor for infants and youngchildren who are too weak or ill to undergo major open surgery. A lessinvasive therapy, i.e., percutaneous heart valve replacement, hasdrastically improved with the development of novel biomaterials andsuggests innovative treatment strategies. There are known in the art thefollowing three percutaneous heart valve (PHV) aortic valve devices:

-   -   (i) The Edwards “SAPIEN” Transcatheter Heart Valve (THV) is made        of cow tissue attached to a stainless steel mesh frame with a        polyester wrap, and it requires 22-24 Fr (˜8 mm) catheter for        delivery for 23-26 mm in diameter;    -   (ii) The Medtronic “CoreValve” is made of porcine pericardial        valve sutured within a three-level self-expanding frame and, it        is delivered via 18 Fr catheter for 20-29 mm in diameter and has        been used to treat inoperable aortic stenosis;    -   (iii) The Medtronic “Melody” pulmonary valve is made of natural        venous tissue with metallic stent and, it is delivered via 22 Fr        catheter for larger than 16 mm in diameter and is used to treat        pulmonary valve replacement for both pediatric and adult        patents.

While percutaneous heart valve replacement is an emerging technologywith a few commercially available devices, these known devices requirevery bulky catheters due to the materials used in the valves (e.g.,bovine, porcine or human tissues), which may not be suitable forpediatric patients. Not only are these valves not “off-the-shelf”products that retain their ideal strength and properties duringlong-term storage and function successfully after replacement, but thevalves will also not grow with the growth of a child.

Ventricular Septal Defects

Congenital cardiac malformations are the most common form of congenitaldiseases, afflicting ˜1% of all live births. Congenital intracardiacshunts are very common in children with congenital heart disease (CHD),ventricular septal defects of some form occur in ˜50% of patients withCHD. Such lesions often lead to shunting of blood to the low resistancepulmonary circulation. Infants without pulmonary stenosis often sufferfrom increased pulmonary blood flow and congestive heart failure.Surgical banding of the pulmonary artery is a palliative procedure meantto decrease pulmonary blood flow and pulmonary artery pressure, thereby“protecting” the lungs against development of elevated vascularresistance and reducing the volume overload to the systemic ventricle.In the current era, pulmonary artery banding is carried out in infantswith large non-restrictive ventricular septal defects and inuniventricular physiology is when partial or total routing of systemicvenous return to the pulmonary circulation is not advisable. The bandingis typically performed in the first few weeks to months of life andfollowed eventually by surgical repair (e.g. closure of the ventricularseptal defect). Banding continues to require an invasive surgicalapproach including a midline sternotomy and occasionally needs to bedone with the use of cardiopulmonary bypass. Despite advances insurgical techniques, significant rates of morbidity and mortalityremain. The disruption in children's lives, and the interruptions intheir socialization and development in their homes and communities arealso significant.

Moreover, in patients that do not go on to early definitive surgicalrepair, the long-term durability of pulmonary artery bands has beenquestioned, and a gradual “loosening” of the band with resultantpulmonary hypertension can occur. Moreover, optimal intra-operativeadjustment of the band tightness is challenging. Patients withinadequate bands at the time of definitive surgical repair have anincreased risk of mortality. In the majority of patients that survivethe banding operation there is significant morbidity associated with thepost-operative recovery from open-chest pulmonary artery banding.Children have significant pain from the surgical incision, are requiredto stay in the intensive care unit (ICU) for many days, and oftenrequire prolonged ventilation. Consequently, they are vulnerable to ahost of surgical complications including (but not limited to) bleeding,chylothorax, diaphragm paresis/paralysis, mediastinal infection, sepsis,pleural effusion and pneumothorax. Both the children requiringmultiple/serial surgeries and their families are adversely affected bythe prolonged rehabilitation from each surgery. Transcatheter ornon-surgical pulmonary artery banding is now a reality. A transcatheterbulk nitinol flow restrictor has been developed by AGA Corp (GoldenValley, Minn.) and used in the clinical setting, however, this device isbulky, thrombogenic, becomes completely obstructive in a matter ofmonths and therefore must be surgically removed within 6 weeks ofimplantation.

The development of a pulmonary artery band amenable to placement in evensmall children with transcatheter technology, rather than with surgery,would dramatically improve the recovery and rehabilitation of childrenfollowing banding.

Coronary Artery Disease (CAD)

Coronary artery disease (CAD) is the most common type of heart diseaseand the leading cause of death worldwide. The disease is caused byplaques building up in the coronary arteries, which narrows the arteryand prevents adequate blood supply to the myocardium. CAD wasresponsible for approximately 20% of all deaths in 2005 in the UnitedStates, according to the American Heart Association. Among theinterventions to restore blood flow, angioplasty (removal or compressionof the plaque by use of catheter, balloon or stent) and bypass grafting(detouring around the blockage) are mostly well established methods fortreating CAD. In 2006, 652,000 patients in the US were treated usingcoronary intervention surgery with stent implantation with anapproximately total cost of $31 billion.

Clinically applied bare metal stents (BMS) are usually made ofnon-degradable metallic materials, such as 316 stainless steel, Ta,cobalt-chromium alloy and titanium alloy. The initial clinical resultsof BMS are generally quite attractive, however re-narrowing of thetreated artery is commonly observed in 20-30% of patients. Thisre-narrowing of the treated artery is due to restenosis, which resultsfrom excessive smooth muscle proliferation. Besides, acute occlusion bythrombosis presents another limitation in the application of BMS. Drugeluting stent (DES) has been developed by incorporatingantiproliferative agents and markedly improved clinical outcomes byreducing the rate of restenosis. The sirolimus eluting Cypher stentusing stainless steel and a biostable polymer coating (Cordis/J&J)received FDA approval in 2003. Afterwards, the paclitaxel eluting Taxusstent (Boston Scientific), the zotarolimus eluting Endeavor stent(Medtronic), and XIENCE V™ everolimus drug eluting stent (Abbott) wereapproved for clinical trials by the FDA.

Long term placement of a non-degradable stent, including the DES, couldstill cause discomfort and provide a source for thrombosis and fibrosisin patients. Also, it provides challenges for subsequent surgical orintravascular interventions. To address such limitations, biodegradablemetallic stents have been developed with their potential to provide thenecessary acute mechanical support, followed by degradation to avoid thecomplications associated with foreign body reactions. Magnesium alloyshave engendered great interests as materials to produce bioabsorbablemetallic stents in coronary arteries, with the benefit of less localinflammation, reduced platelet adhesion and less neo-intima formationthan traditional non-biodegradable metallic stents. Goodbiocompatibility has been demonstrated in porcine coronary artery model.Clinical studies also showed feasibility, good safety profile, andpromising angiographic performance.

Recently, new generation of stent systems, called covered stents havebeen developed. A thin membrane is used to cover the interior luminal oradluminal surface of the stents. Currently, most commercially availablecovering membranes are usually made of non-degradable ePTFE thin film.The thin membrane not only decreases the radial pressure of the stent,but also reduces the restenosis and re-embolization by acting as thebarrier between the vessel wall and the blood stream. In addition, thethin membranes can serve as drug release reservoir.

Peripheral Arterial Disease (PAD)

Lower extremity peripheral arterial disease (PAD) represents asignificant disease burden in the United States. Epidemiological studieshave estimated the prevalence of PAD at between 3-10% with an increaseto 10-15% in persons over 70 years. Industry wide estimates suggest thatfor femoral and popliteal disease alone, there will be an increase to1.7 million procedures by 2020. Current treatment trends for PAD includean expanding role for endovascular procedures to revascularize ischemiclimbs as compared to open bypass. Recently a randomized trial inpatients with chronic limb ischemia revealed no difference in amputationfree survival at one year between endovascular versus open bypasssurgery. However, open surgical repair using vein graft remains the goldstandard of treating complex lesions in the extremities due to betterlong term patency (i.e. reduced thrombogenicity). Therefore, a criticalneed exists for developing endovascular technology to treat PAD that isnon-thrombogenic or at least comparable to vein grafts.

Two common approaches currently used to treat PAD include bypass usingautologous vein grafts and endovascular placement of polymer coatedstents. While autologous vein grafts remain patent longer than expandedpolytetrafluoroethylene (ePTFE) grafts (5 year patency of 74-76% versus39-52% for above the knee femoral popliteal bypass), there are stillsignificant thrombotic complications. These thrombotic complicationsrepresent the key problem in the continued treatment and management ofPAD. Approximately one third of patients in both groups developedthrombosis requiring re-intervention with attempts at mechanicalthrombectomy and/or bypass grafting. Therefore, graft thrombosis issignificant and represents the major obstacle in treating PAD.Furthermore, the cost increases by a factor of 2 to 4 times when theinitial treatment plan fails regardless of the approach used. Therefore,any technology that ameliorates or prevents endograft thrombusdevelopment will have a significant impact on patient quality of lifeand functional status not to mention a profound impact on decreasing theamount of health care dollars spent on PAD.

Excessive Hemorrhage

There is an immediate need for developing advanced catheter-baseddevices to prevent excessive hemorrhage in wounded soldiers at triagelocations near the battlefield. Therefore, the invention provides bothan ultra-low profile catheter-based vascular occluder for percutaneoustreatment of massive hemorrhage and also covered stents for later,definitive repair of vascular injuries.

It is currently estimated that extremity injury is the leading cause ofpreventable deaths on the battlefield, with estimates of up to 79% beingpreventable with adequate control of bleeding. The majority of theseinjuries require vascular repair that involve peripheral arteries (armsand legs). Rapid, minimal invasive control of bleeding prior todefinitive repair would reduce mortality and morbidity in most of thesecases. Therefore, there is an immediate need in battlefield situationsfor vascular injury control devices. In general, these devices shouldeither prevent the bleeding by isolating the injury or provide a conduitfor repair of the vascular system. New low profile concepts will havesubstantial military and civilian applications for the treatment oftrauma, iatrogenic injury, aneurysmal disease and other internalvascular related conditions.

Thus, there is a need in the art to develop endovascular devices andmaterials that provide improved mechanical properties andbiodegradability as implant devices for use in medical conditions anddiseases such as, but not limited to, pediatric heart diseases, coronaryartery disease, peripheral arterial disease and excessive hemorrhage.

SUMMARY OF THE INVENTION

In one aspect, the invention provides an endovascular medical implantdevice including a structural frame constructed of a plurality ofelongated pieces composed of biodegradable metal and, one or moreconnectors composed of superelastic material and structured to jointogether the plurality of elongated pieces. The medical implant devicefurther includes a deposition material selected from biodegradablepolymer, thin film nitinol and, mixtures and combinations thereof, whichis deposited on at least a portion of the structural frame.

The superelastic material can include nitinol. The biodegradable metalcan be selected from the group consisting of magnesium, iron and, alloysand mixtures thereof. The biodegradable polymer can be selected from thegroup consisting of polyester, polyurethane urea, polycaprolactone,poly-L-lactic acid, polyglycolic acid and mixtures thereof. In certainembodiments, the biodegradable polymer is in a form selected from amembrane applied to a backbone of the structural frame and a coatingdeposited on the plurality of elongated pieces composed of biodegradablemetal. The coating can include electrospun fibers formed byelectrospinning.

The structural frame can be elastically deformable from an original formto a collapsed structure. The collapsed structure can be placed in adelivery tube, deployed from the delivery tube into a patient body andupon being deployed, the collapsed structure can recover to the originalform. The delivery tube can be a catheter or other tube that mimics ablood vessel. In certain embodiments, the tube is composed of silicone.

The plurality of elongated pieces of the structural frame can beselected from the group consisting of wires, strips and, combinationsand mixtures thereof.

In certain embodiments, the superelastic material is nitinol, thebiodegradable metal is selected from magnesium, magnesium alloy, iron,iron alloy and mixtures thereof, and the deposition material is selectedfrom thin film nitinol (not bioabsorbable), polyurethane urea membrane,and mixtures and combinations thereof. The nitinol can constitute about10% or less by weight, the biodegradable metal can constitute about 80%or greater by weight, and the deposition material can constitute about5% or less, or about 10% or less by weight, based on total weight of thedevice.

In another aspect, the invention provides a method of preparing anendovascular device. The method includes forming a structural frame byobtaining a plurality of elongated pieces composed of biodegradablemetal, obtaining one or more connectors composed of superelasticmaterial, and employing the one or more connectors to join together theplurality of elongated pieces to form the structural frame, anddepositing a deposition material selected from thin film nitinol,biodegradable polymer and, mixtures and combinations thereof on at leasta portion of the structural frame.

The depositing of the deposition material can include applying abiodegradable polymer membrane to a backbone of the structural frame,applying a nitinol thin film to a backbone of the structural frame, ordepositing a biodegradable polymer coating on the plurality of elongatedpieces composed of biodegradable metal. In certain embodiments, thecoating is composed of polyurethane urea electrospun fibers.

The method can further include elastically collapsing the structuralframe from an original form to a collapsed structure, inserting thecollapsed structure in a delivery tube, deploying the collapsedstructure from the delivery tube into a vascular target in a patientbody, and recovering the original form of the structural frame in thevascular target.

The one or more connectors can be applied to the plurality of elongatedpieces using a mechanism selected from the group consisting ofmechanical clamping, gluing, suturing, and micro-laser welding.

The endovascular device can be integrated into a stent delivery cathetersystem.

BRIEF DESCRIPTION OF THE DRAWINGS

A full understanding of the disclosed concept can be gained from thefollowing description of the preferred embodiments when read inconjunction with the accompanying drawings, in which:

FIG. 1A is an image showing a stent frame structure composed ofbiodegradable metal wires integrated with superelastic materialconnector segments;

FIG. 1B is an image showing a detailed view of an integratedbiodegradable metal wire and superelastic material connector (tube) asshown in FIG. 1A;

FIG. 1C is an image showing a detailed view of the superelastic materialconnector segment (tube and strut) as shown in FIG. 1A;

FIG. 2A is the image of FIG. 1A, further showing a biodegradable polymercoating formed on the biodegradable metal wires;

FIG. 2B is an image showing a detailed view of the biodegradable polymercoating, in the form of electrospun fibers, formed on the biodegradablemetal wire as shown in FIG. 2A;

FIG. 2C is an image showing a detailed view of the electrospun fibers onthe biodegradable metal wire as shown in FIG. 2B;

FIG. 3A is an image showing a stent frame structure, with a leaflet,collapsed in a silicone tube;

FIG. 3B is a top view of FIG. 3A;

FIG. 3C is a side view of FIG. 3A;

FIG. 4A is an image showing the outer surface of a vascular occlusionframe, composed of a biodegradable polymer membrane;

FIG. 4B is an image showing the inside surface of the vascular occlusionframe shown in FIG. 4A, including the biodegradable metal wires andsuperelastic material connector segments;

FIG. 5A is an image showing a stent graft frame, including abiodegradable polymer membrane applied to the backbone of the frame;

FIG. 5B is an image showing the inside surface of the stent graft frameshown in FIG. 5A, including the biodegradable metal wires andsuperelastic material connector segments;

FIG. 5C is an image showing the biodegradable polymer membrane outsidesurface of the stent graft frame shown in FIG. 5A;

FIG. 6A is an image showing a biodegradable polymer coating (on abiodegradable metal wire as shown in FIG. 2A) and an integratedsuperelastic material connector (tube);

FIG. 6B is an image showing the presence of the biodegradable metal wirein the biodegradable polymer coating as a portion of the biodegradablemetal wire degrades over a period of time; and

FIGS. 7A, 7B, 7C and 7D are images showing a stent structural frameworkthat was implanted at a target location and the degradation of thebiodegradable metal wire after one month.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The invention relates to superelastic, bioabsorbable endovasculardevices, biodegradable materials for their construction, methods forpreparation and uses as medical implant devices.

A key aspect of this concept is the combination of small, highlyelastic, non-degradable connection pieces, with structural elements andbioactive components made from degradable metals and polymers. Theintegration of more than one, e.g., two or three, implantablebiomaterials together with novel manufacturing approaches can result inthe formation of a variety of endovascular devices applicable to manylife-threatening vascular diseases, with particular applications in thepediatric and geriatric populations. The devices are constructed andformed of a combination of materials selected from a superelasticmaterial, e.g., a metal alloy, a biodegradable metal and a biodegradablepolymer or a thin film nitinol.

In certain embodiments, the endovascular devices can include a skeletalstructure, e.g., frame structure or framework, which is composed ofbiodegradable metal and superelastic material, that has a depositionmaterial, such as, biodegradable polymer or thin film nitinol (notbioabsorbable), applied or deposited thereon. The biodegradable metalcan be in the form of a plurality of individual elongated, e.g.,straight, pieces or segments, such as wires, strips and combinations ormixtures thereof. The superelastic material can be in the form ofconnector pieces or segments, e.g., wires, struts or tubes, tointegrate, join or connect together the individual biodegradable metalelongated pieces or segments. For example, one end of a firstbiodegradable metal piece or segment can be connected to an end of asecond biodegradable metal piece or segment by use of a superelasticconnector, e.g., tube and/or strut, positioned between these two ends.The superelastic connector can be applied to the biodegradable metalsegment using a variety of mechanisms, such as, but not limited to,mechanical clamps, adhesive (e.g., glue), sutures (e.g., thread) andmicro-laser welding.

FIG. 1A shows a stent frame structure 1 constructed of a plurality ofstraight, biodegradable metal wires 2 integrated with superelasticmaterial connector tubes 4. FIG. 1B shows a detailed view of one of themetal wires 2 integrated with one of the superelastic material tubes 4.FIG. 1C shows a detailed view of the metal wires 2 integrated with thesuperelastic material tubes 4, which are joined by a superelasticmaterial (v-shaped) strut 3.

The metallic portion of the frame structure provides sufficientmechanical force with a low-profile design, maintains the geometry ofthe device structure, and is biocompatible. Additionally, in accordancewith the invention, the elongated pieces or segments are composed of abiocompatible metal that is also biodegradable. Non-limiting examples ofbiodegradable metals for use in constructing and forming the metallicframe include, but are not limited to, magnesium, magnesium-based alloy,iron, iron-based alloy, and mixtures thereof. The biodegradable metalconstitutes about 80% or greater or about 90% or greater of the totalmass of the endovascular device.

Biodegradable materials such as magnesium, magnesium-based alloys, ironand iron-based alloys are attractive as alternatives for permanentmetallic devices, because they can resorb through oxidation over aspecific period of time. Magnesium alloys remain in the body only for aslong as is needed for them to perform their specific functions (e.g.,maintaining geometry of skeletal structures or exerting mechanicalforces). Beyond the expected period of time for functioning, themagnesium alloys gradually degrade and finally disappear. This temporaryexistence can reduce or potentially eliminate the long-termcomplications or risk of medical implant devices, such as in-stentrestenosis, infections, or mechanical instability in cases of pediatricpatients. Magnesium shows biocompatibility and low thrombogenicity.Although, these biodegradable materials have potentially attractivelong-term biocompatibility, there are significant limitations associatedwith these materials. Iron has a slow degradation profile and, aspreviously mentioned, magnesium does not possess sufficient mechanicalproperties (i.e., ductility) for endovascular devices.

The superelastic material for use in the invention includes a metalalloy, such as, but not limited to, nickel-titanium alloy (known as“nitinol”), which is used to form miniature connections within theendovascular device of the invention. The connections can be in the formof tubes or struts, e.g., v-shaped struts. Nitinol is a preferred metalalloy due to its shape memory property (“superelastic” property). Theshape memory response is defined as a mechanical (elastic) deformationin a low temperature state (i.e., martensite) with deformations fullyrecovered when the material is heated to body temperature (i.e.,austenite). This shape memory behavior of nitinol is critical fortranscatheter devices because the metallic frame composed of nitinol caneasily be collapsed into a small diameter catheter (or any tube thatmimics a blood vessel) in its martensite phase. Upon an exposure toblood temperature, the collapsed nitinol metallic frame deploysspontaneously to its original shape (i.e., the austenite phase). Becausethe magnitude of recoverable elastic deformation of nitinol is muchgreater than elastic deformation of other metals, such as surgicalsteel, nitinol-based devices can be placed into remarkably smallerdiameter catheters for a wide range of catheter-based procedures.However, a disadvantage associated with nitinol is that it remains inthe circulatory system permanently (it is not biodegradable) andsometimes increases the risk of thrombosis, infections, and restenosis.Thus, an endovascular device in accordance with the invention constituteabout 10% or less of nitinol, based on the total mass of the device.

Further, in accordance with the invention, at least a portion of theskeletal structure has deposited thereon or applied thereto a depositionmaterial selected from biodegradable polymer, thin film nitinol and,mixtures and combinations thereof.

The biodegradable polymer includes, but is not limited to, polyester,polyurethane urea and, blends and combinations thereof, and constitutesabout 10% or less of the total mass. The biodegradable polymer can be inthe form of a coating or membrane that covers at least a portion of thebiodegradable metal, due to their low profile feature andbiocompatibility.

Commercially available polymeric biomaterials suitable for use in theinvention include ePTFE, Dacron, polycaprolactone (PCL), poly-L-lacticacid (PLLA), polyglycolic acid (PGA) and, mixtures and combinationsthereof. Some polymeric biomaterials, e.g., ePTFE and Dacron, are notdegradable. Certain polyurethane ureas (PUUs) have been shown to possessgood biocompatibility with non-toxic degradation products and highelasticity and strength, even in very thin (<1 mm) formats.

PUUs include soft segments (polycaprolactone, polyethylene glycol,polycarbonate, and the like), diisocyanatebutane and chain extenderputrescine. In certain embodiments, PUU copolymer is prepared by atwo-step polymerization process whereby polycaprolactone diol,1,4-diisocyanatobutane, and diamine are combined in a 1:2:1 molar ratio.In the first step, a pre-polymer is formed by reacting polycaprolactonediol with 1,4-diisocyanatobutane. In the second step, the pre-polymer isreacted with diamine to extend the chain and to form the final polymer.The degradation profiles and mechanical properties can be tailored orpre-selected by changing the molecular weight and the composition of thesoft segments. A thermoplastic elastomer is easy to process into variousdifferent shapes. Of specific interest to tissue engineeringapplications, porous scaffolds can be made from polyurethanes usingfabricating processes, such as, thermally induced phase separation, saltleaching, and electrospinning.

In certain embodiments, the biodegradable polymer is deposited in theform of a coating on at least a portion of the frame structure, e.g., onthe biodegradable metal segments. The coating can be in the form ofelectrospun fibers. PUU can be directly deposited onto the metallicframe by using various conventional apparatus and techniques known inthe art, such as but not limited to, electrospinning. Electrospinning isa well-established method for producing polymeric micro- andnano-fibers, which includes utilizing electrostatic forces to uniaxiallystretch a viscoelastic jet derived from a polymer solution or melt intofibers with small diameters, e.g., forming fibrous mats. Themicro-morphology of the fibrous mats can be tailored by varying thepolymer solution concentrations, the polymer molecular weight, the feedrate of the polymer solutions, the distance from the source to thetarget, the voltage between the source and the target, and therotational speed of the collecting mandrel. The resulting electrospunfibrous mats made from PUU have the appearance of a white, nonwovenfabric.

FIG. 2A shows the stent frame structure as shown in FIG. 1A and furtherincludes a biodegradable coating 5 deposited on the biodegradable metalwires 2 (shown in FIG. 1A). FIG. 2B is a detailed view showing one ofthe metal wires 2 having deposited thereon the biodegradable coating 5,which includes electrospun fibers. FIG. 2C is a detailed view of theelectrospun fibers that compose the biodegradable coating 5 (as shown inFIGS. 2A and 2B).

The thin film nitinol for use in the invention can includemicro-patterned thin film nitinol, which is connected onto the skeletalstructure or backbone, for example, by stitching with ultra-fine nitinolthread (e.g., about 22 μm thickness), such as for heart valve leaflets.The thin film nitinol can be fabricated using conventional processes andapparatus known in the art. In certain embodiments, suitable thin filmnitinol for use in the invention is fabricated by a DC sputterdeposition technique using a near equiatomic nitinol target underultra-high vacuum atmosphere. “Hot-target” sputter deposition andmicropatterning to create thin film nitinol with fenestrations can beconducted as follows. Photoresist is deposited on a (4-inch) siliconwafer in a desired or pre-selected micropattern. A deep reactive ionetching technique is used to create trenches (50 micrometers in depth)around the photoresist. The etching rate varies and can be approximatelyone minute for each one micrometer in depth. After removing thephotoresist layer, a sacrificial layer of copper followed by aninhibitory silicon dioxide layer are deposited. Then, the thin filmnitinol is sputter deposited on sheets (6 micrometer in thickness) andremoved from the silicon oxide layer. Following deposition and removal,the film is crystallized for (120 minutes at 500° C.) in a vacuum (ofless than 1×10⁻⁷ torr). The thin film nitinol material used in theinvention can have an austenite finish temperature of about 34° C. Thefilm can then undergo a final cleaning treatment consisting ofsequential rinsing in acetone, methanol, and ethanol (for five minutes)prior to use.

As described herein, the superelastic material, e.g., nitinol, is usedto form miniature connectors for joining biodegradable metal segments inthe skeletal structure of an endovascular device, to allow the device tobe deformed and then return to its original shape. In its deformedstate, the collapsed skeletal structure is inserted into a delivery tubeand then deployed at a vascular target site within the body of apatient. The delivery tube can include any tubing that mimics a bloodvessel, such as, but not limited to, a delivery catheter. Further, thedelivery tube can be composed of a variety of known materials for thispurpose. In certain embodiments, the delivery tube is silicone tubing.Upon deployment, the skeletal structure returns to its original, e.g.,expanded, state. The skeletal structure can be, for example, a stent andstent graft.

The deposition material, thin film nitinol and/or biodegradable polymermaterial, can be used as scaffolds for soft tissue development, such asvalve leaflets. In certain embodiments, nitinol thread can be used tostitch thin film nitinol or PUU membrane onto the metallic frame forheart valve leaflets.

FIG. 3A is a front view showing a collapsed stent frame structure 1 anda single leaflet 6. A suture (not shown) is used to attach the leafleton the backbone of the stent frame structure 1. The stent framestructure 1 is collapsed inside a delivery tube 7. FIG. 3B is a top viewof the delivery tube 7 and the leaflet 6 contained therein, and FIG. 3Cis a side view of the delivery tube 7 containing the collapsed stentframe structure 1 with the leaflet 6 attached thereto.

In certain embodiments of the invention, a vascular occlusion frame canbe constructed using the biodegradable metal segments and thesuperelastic connector segments. In this embodiment, a biodegradablepolymer membrane is deposited on or applied to the frame (in a pyramidalshape) to form an outer surface thereon. FIGS. 4A and 4B shown avascular occlusion frame including a biodegradable polymer membrane 8.FIG. 4A shows the outer surface of the frame, which is composed of thebiodegradable polymer membrane 8. FIG. 4B shows the inside surface ofthe frame, including the biodegradable metal wires 2 and thesuperelastic connecter tubes 4.

FIGS. 5A, 5B and 5C show a stent graft frame, in accordance with certainembodiments of the invention. As shown in FIGS. 5A and 5C, there is thebiodegradable polymer membrane 8 deposited on or attached to a backboneof the stent graft frame. FIG. 5B shows the inner surface of the stentgraft frame, including the biodegradable metal wires 2 and thesuperelastic connector segments 4.

Without intending to be bound by any particular theory, it is believedthat the presence of a biodegradable polymer coating on a biodegradablemetal wire increases its length of time for degradation. FIG. 6A showsthe biodegradable polymer coated wire and superelastic tube as shown inFIGS. 2B and 2C, wherein the biodegradable wire 2 has deposited thereonthe biodegradable polymer coating 5 that is composed of electrospunfibers. FIG. 6B shows that after a period of time a portion of thebiodegradable metal wire 2 is degraded. The wire is degraded and theremaining electrospun fiber coating is effective to support thestructure.

In certain embodiments, the endovascular devices of the invention arecomposed of a combination of nitinol, magnesium and polyurethane urea(PUU). Each of these materials, individually, is known in the art as abiomaterial for use in medical devices. For example, individually,nitinol is known for use in constructing self-expanding devices and,individually, magnesium is known for constructing biodegradable devices.These devices that contain nitinol only or magnesium only have beenfound to exhibit a lack of ductility However, in accordance with theinvention, nitinol, magnesium and PUU are combined, e.g., integrated, toform endovascular devices that demonstrate self-expanding andbioabsorbable properties.

In accordance with the invention, endovascular devices are constructedof a combination, e.g., integration, of metal alloy (superelasticmaterial), biodegradable metal and, biodegradable polymer and/or thinfilm nitinol. In certain embodiments, the endovascular devices include acombination of nitinol, magnesium (or magnesium alloy or iron or mixturethereof) and PUU or thin film nitinol. These devices are elasticallydeformable and collapsible to a small diameter, e.g., for catheter-baseddelivery, and deployable in conduits that serve the vasculature invitro. Thus, these three materials can be integrated, collapsed,delivered and deployed. In certain embodiments, the endovascular devicesinclude frames formed of straight pieces or segments composed ofbiodegradable metal (e.g., magnesium/magnesium alloy), which areconnected by a superelastic material (e.g., nitinol) to form a skeletalstructure that is covered with a polymer membrane (e.g., PUU) or thinfilm nitinol.

Benefits and advantages of endovascular devices composed of theintegration of nitinol, magnesium and, PUU and/or thin film nitinol, ascompared to conventional materials for use in constructing endovasculardevices, include one or more of the following:

-   -   (i) gradual integration with tissue, e.g., tissue growth at the        deployment site offsets the loss of mechanical properties with        the degradation of magnesium;    -   (ii) ultra-low profile design since the fabrication process is        ideally suited for highly tortuous cerebral arteries or weakened        arteries;    -   (iii) ballooning is not required for the deployment of a stent,        stent graft, and heart valve, which reduces potential blood        vessel injuries and embolization of broken atherosclerotic        plaque (e.g., for balloon angioplasty);    -   (iv) tailoring of mechanical properties;    -   (v) customization of the initial and final geometry; and    -   (vi) minimal residue of the vascular devices (e.g., only nitinol        connections will remain, less than 10% of the total mass of the        endovascular device).

Optionally, the metal alloy, biodegradable metal and deposition material(biodegradable polymer and/or thin film nitinol) can be combined, e.g.,integrated, with other materials, such as, but not limited to, glue,suturing materials, other metallic wires, and welding materials. Interms of geometry of the endovascular devices, they should besufficiently low profile and conformally deployed without disruptingblood flow after the placement in the circulatory system. Metallic framecomponents, such as wires and strips, can be manufactured by eitherconventional or advanced manufacturing processes. For example, powdermetallurgy or electroforming are used for producing magnesium wires orstrips, and powder metallurgy, heat annealing, and, potentially, lasercutting processes are used for producing nitinol wires or strips. Theseconventional fabrication processes and the apparatus used therewith arecommercially known.

In certain embodiments, the endovascular devices of the invention may befabricated in the absence of glue, suturing materials, other metallicwires and welding materials. These embodiments include microscalemechanical clamping (or insertion) of nitinol and magnesium, and directdeposition of PUU and/or thin film nitinol onto a backbone metallicframe structure. In certain embodiments, nitinol and magnesium areconnected by inserting magnesium wire into a nitinol tube and then,mechanically clamping or using a small amount of biocompatible polymeradhesive. For the micro-patterned thin film nitinol or PUU membrane, anultra-fine nitinol thread (i.e., 22 μm thick) can be used to connect thefilm or membrane onto the nitinol-magnesium metallic frame.

The fabricated endovascular device according to the invention can beintegrated and deployed into a wide variety of systems to target adiverse set of medical conditions and diseases. For example, after theendovascular device has been fabricated, it can be successfullyintegrated into a stent delivery catheter system. In certainembodiments, the device is initially cooled to below 5° C., to allow thenitinol material to be easily deformed (i.e., converting to a malleablemartensite phase in nitinol). Once the device is deformed into acollapsed geometry, the device is inserted into the delivery catheter.Deployment may be achieved through a pushrod passed through the deliverycatheter. Standard off-the-shelf delivery systems can be used to deploythe devices in vivo and in vitro. Upon the device being deployed andexposed to the blood temperature (i.e. in-vitro and in-vivo), the deviceconformally deploys in the vascular lumen (i.e., converting to the fullyrecovered austenite phase in nitinol).

In accordance with the invention, the combination and integration ofsuperelastic and biodegradable materials, e.g., components, allows atissue engineering approach to be pursued where no permanent foreignbody is left behind other than small nitinol pieces. FIGS. 7A, 7B, 7Cand 7D show that a stent structural framework was implanted at a targetlocation and after one month, the biodegradable iron wire haddisappeared.

In some settings (e.g. esophagus) the remaining pieces may dislodge andbe cleared by the body. In other instances (e.g., cardiac septum) thesuperelastic components, e.g., nitinol connectors, are encapsulated inthe developing soft tissue. Thus, constrictive geometries that are notcapable of growing with a child are avoided (e.g., in stents) and therisk of infection, fibrosis or abrasion from left behind structures arealso minimized. Further, healing or new tissue growth may be achievedwith these devices over a time period from weeks to months.

According to the invention, the integration of nitinol, magnesium andPUU can be employed to provide the following medical devices:

1) Cardiovascular/peripheral artery stents or stent grafts for vascularreconstruction or the treatment of diseased segments;

2) Ultra-low profile intracranial aneurysm stents;

3) An atrial septal defect (ASD) closure device for treating the heartwall defects;

4) An inferior vena cava (IVC) filter for treating venousthromboembolism;

5) Vascular plugs or occluders for temporarily treating hemorrhage orfor embolic treatment in cancer;

6) Carotid artery stent grafts for isolating atherosclerotic plaque;

7) Esophageal healing stents to temporarily hold surfaces such asextracellular matrix based materials against the stripped esophagealwall; and

8) An ultra-low profile pediatric heart valve that may have thepotential to grow with a child.

In general, the invention is applicable to adult and pediatricapplications where a temporary need exists to provide scaffolding withmechanical support. The medical implant devices, e.g., endovasculardevices, constructed and formed in accordance with the invention areeffective to provide support acutely. These devices can include nitinolin an amount that constitutes about 10% or less of the total mass, andbiodegradable material (that disappears over a specified period of time)in an amount that constitutes at least about 90%. Target applications orconditions include congenital patent ductus arteriosus, aortic archrepair for restenosis of post-coarctation, pulmonary artery (PA)stenosis in post-PA plasty or BT shunt stenosis in children, systemicvenous stenosis (post Fontan operation).

EXAMPLES

Two different material stent graft groups, i.e., Group 1 and Group 2,were compared following implantation in abdominal aorta of rabbit. NewZealand White rabbits weighing about 3.5 kg were used. A midlineabdominal incision was made to expose the infrarenal aorta. The aortawas clamped, an aortotomy was performed, and a catheter with stentinside was inserted into the aorta. The stent was then successfullydeployed. No damage or expansion was observed on the aorta wall afterstent deployment. In Group 1, the stent was a PUU monocusp, e.g.,leaflet, with iron-nitinol frame. In Group 2, the stent was aniron-nitinol frame, without the leaflet. Group 2 served as a control toeliminate the effects of the valve, which may have thrombogenicity dueto disturbed flow effects that are independent of the supporting stentstructure. The in vivo studies had 1 week and 1 month endpoints for eachgroup. At the 1 week endpoint, acute thrombogenicity and placementstability was evaluated. Gross examination of the artery showed noembolism and no signs of abnormalities. Neither migration nor collapsewas observed for the stent. Histology studies showed that there was asmall layer of membranous thrombus covering the stent struts. Theinterface between the aorta and the metallic struts showed accumulationof brownish iron debris and the luminal surface adjacent to the stentstruts had a brownish tinge. Iron laden macrophages or lymphocytes,ranging from a sparse isolated localization to accumulation in clusters,were found close to the stent struts. At the 1 month endpoint, earlyremodeling characteristics of the monocusp valves and stent graft wasevaluated. The iron stent struts were integrated into the artery wall,with both nitinol and iron parts covered completely with a neointima.Adjacent to the iron stent struts, there were accumulation ofdegradation products accompanied by macrophages.

Whereas particular embodiments of the invention have been describedherein for purposes of illustration, it will be evident to those skilledin the art that numerous variations of the details may be made withoutdeparting from the invention as set forth in the appended claims.

What is claimed is:
 1. An endovascular medical implant device,comprising: a structural frame, elastically deformable from an originalstructure to a collapsed structure, comprising: a plurality of elongatedsegments composed of biodegradable metal, wherein the biodegradablemetal constitutes about 80% or greater of the total mass of the device;one or more connectors composed of nitinol structured to join togetherthe plurality of elongated segments, wherein a total of the nitinolconstitutes about 10% or less of the total mass of the device; and amaterial comprising biodegradable polymer applied to at least a portionof the structural frame, wherein the biodegradable polymer constitutesabout 10% or less of the total mass of the device, and wherein one ormore pairs of the plurality of elongated segments are connected togetherby the one or more connectors to form the structural frame.
 2. Theendovascular medical implant device of claim 1, wherein thebiodegradable metal is a metal wire.
 3. The endovascular medical implantdevice of claim 1, wherein the biodegradable polymer is in a formselected from the group consisting of coating, sheet and combinationsthereof.
 4. The endovascular medical implant device of claim 3, whereinthe coating comprises electrospun fibers.
 5. The endovascular medicalimplant device of claim 1, wherein the one or more connectors is in aform selected from the group consisting of strut, wire, tube andcombinations thereof.
 6. The endovascular medical implant device ofclaim 1, further comprising a mechanism to apply the one or moreconnectors to the plurality of elongated segments, the mechanismselected from the group consisting of mechanical clamps, adhesive,sutures, micro-laser welding and combinations thereof.
 7. Theendovascular medical implant device of claim 1, wherein the collapsedstructure is placed in a delivery tube, the collapsed structure isconfigured to be deployed from the delivery tube into a patient body andupon being deployed, the collapsed structure recovers the originalstructure.
 8. A method of preparing an endovascular device, comprising:forming a structural frame, comprising: obtaining a plurality ofelongated segments composed of biodegradable metal; obtaining one ormore connectors composed of nitinol; employing the one or moreconnectors to join together the plurality of elongated segments to formthe structural frame; and applying a biodegradable polymer to at least aportion of the structural frame, wherein the biodegradable metalconstitutes about 80% or greater of the total mass of the device,wherein a total of the nitinol constitutes about 10% or less of thetotal mass of the device, wherein the biodegradable polymer constitutesabout 10% or less of the total mass of the device, and wherein one ormore pairs of the plurality of elongated segments are connected togetherby the one or more connectors to form the structural frame.
 9. Themethod of claim 8, wherein the applying the biodegradable polymer isselected from applying a biodegradable polymer membrane to a backbone ofthe structural frame, and depositing a biodegradable polymer coating onthe plurality of elongated segments.
 10. The method of claim 8, furthercomprising: collapsing the structural frame from an original form to acollapsed structure; inserting the collapsed structure in a deliverytube; deploying the collapsed structure from the delivery tube into avascular target in a patient body; and recovering the original form ofthe structural frame in the vascular target.
 11. The method of claim 8,wherein the employing the one or more connectors to join together theplurality of elongated segments to form the structural frame comprisesusing a mechanism selected from the group consisting of mechanicalclamps, adhesives, sutures, and micro-laser welding.
 12. The method ofclaim 8, wherein the biodegradable metal is a metal wire.
 13. The methodof claim 8, wherein the biodegradable polymer is in a form selected fromthe group consisting of coating, sheet and combinations thereof.
 14. Themethod of claim 13, wherein the coating comprises electrospun fibers.15. The method of claim 8, wherein the one or more connectors is in aform selected from the group consisting of strut, wire, tube andcombinations thereof.
 16. A stent delivery catheter system, comprising:a structural frame, elastically deformable from an original structure toa collapsed structure, comprising: a plurality of elongated segmentscomposed of biodegradable metal, wherein the biodegradable metalconstitutes about 80% or greater of the total mass of the device; one ormore connectors composed of nitinol structured to join together theplurality of elongated segments, wherein a total of the nitinolconstitutes about 10% or less of the total mass of the device; and amaterial comprising biodegradable polymer applied to at least a portionof the structural frame, wherein the biodegradable polymer constitutesabout 10% or less of the total mass of the device, and wherein one ormore pairs of the plurality of elongated segments are connected togetherby the one or more connectors to form the structural frame; a deliverycatheter for receiving the collapsed structure; and a pushrod configuredto deploy the collapsed structure from the catheter to thereby positionthe original structure at a vascular target site.
 17. The stent deliverycatheter system of claim 16, wherein the delivery catheter is a silicontube.
 18. The stent delivery catheter system of claim 16, wherein thebiodegradable metal is a metal wire.
 19. The stent delivery cathetersystem of claim 16, wherein the biodegradable polymer is in a formselected from the group consisting of coating, sheet and combinationsthereof.